Methods of treating ophthalmic disorders

ABSTRACT

Provided is a method for improving day photopic vision and/or cone-derived visual field and visual function in a subject suffering from a retinal disease or trauma including administering to the subject a pharmaceutically effective amount of crude  Dunaliella  powder. Also provided is a method for improving night vision and/or rod derived visual field in a subject suffering from a retinal disease including administering to the subject a pharmaceutically effective amount of crude  Dunaliella  powder. A pharmaceutical composition for improving day vision and/or visual field in a subject suffering from a retinal disease including crude  Dunaliella  powder is also provided.

This is a National Phase Application filed under 35 U.S.C. 371 as anational stage of PCT/IL2009/000448, filed on Apr. 27, 2009, anapplication claiming the benefit under 35 USC 119(e) of U.S. ProvisionalApplication No. 61/071,447, filed on Apr. 29, 2008, and an applicationclaiming the benefit under 35 USC 119(e) of U.S. Provisional ApplicationNo. 61/202,336, filed on Feb. 19, 2009, the content of each of which ishereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

This invention relates to methods of treating ophthalmic disorders, andto pharmaceutical compositions therefor.

BACKGROUND OF THE INVENTION

The human eye is capable of both day and night vision. Rod cells, orrods, are photoreceptor cells in the retina of the eye that can functionin less intense light than can the other type of photoreceptor, conecells. Being more light sensitive, rods are responsible for nightvision. Named for their cylindrical shape, rods are concentrated in allparts of the retina except its center and thus provide peripheralvision. Cone cells, or cones, are photoreceptor cells in the center ofthe retina of the eye which function best in relatively bright light.The cone cells gradually become sparser towards the periphery of theretina.

Diseases of the eye may affect one type of vision or the other or both.In certain diseases, first night vision is affected, while day vision isaffected as the disease progresses.

Retinitis pigmentosa (RP) comprises a group of relatively commoninherited diseases characterized by progressive degeneration of theretina of the eye. The continually spreading destruction of the retinaleads to increasingly severe visual loss. Vision gradually degeneratesfrom the periphery [night vision, wide visual field] to the center [highdefinition day vision, colors]. Symptoms start with a decrease in darkadaptation leading to night blindness. There is a simultaneous reductionin the peripheral field of view up to tunnel vision. Central (day)vision is subsequently lost leading to total blindness. The rate ofprogression of RP varies according to the specific genetic defect. Thevisual impairment problem is much more prevalent than blindness.

Currently, no treatment is recognized to improve the vision of RPpatients. Vitamin A palmitate (15,000 U/d) is prescribed to slow theprogress of RP by about 2% per year. Current clinical trials areunderway to attempt to slow degeneration, and include:

-   -   Ciliary Neurotrophic Factor eye Implant    -   Omega 3 amino acid (DHA)    -   Lutein (10 or 30 mg/day) capsules    -   Vitamin A    -   Vitamin E

Over the last 15 years, researchers have pinpointed defects in dozens ofgenes causing different forms of RP. Surprisingly, in some cases,patients with the same genetic defect can show different severities ofvision loss and rates of disease progression. This effect is mostdramatic across the retina of some individuals where regions with normalvision can abut regions of no vision. Environmental factors have beennear the top of the suspect list for this variation in severity. Anenvironmental factor experienced by all, but to varying extents, isexposure to light bright lights have been previously speculated toaccelerate certain forms of RP.

About 100 mutations in the rhodopsin gene have been shown to cause RPbut understanding of the steps between mutant proteins and death of rodphotoreceptors remains incomplete. Many of the patients with rhodopsinmutation are known to have better prognosis while other suffer fromblindness since early childhood with rapid degeneration.

Another eye disease is Leber's congenital amaurosis (LCA). RP and LCAare not the same disease although a few of the genes are common.

A large majority of blindness and low vision in developed countries isdue to Age Related Macular Degeneration (AMD), a disease which involvesdestruction of the photoreceptors. AMD affects more than 1.75 millionindividuals in the United States. Owing to the rapid aging of the USpopulation, this number will increase to almost 3 million by 2020 (ArchOphthalmol. 2004; 122:564).

Night blindness also occurs in non-degenerative eye diseases. Examplesof such diseases include congenital night vision disorder, congenitalstationary night blindness, fundus albipunctatus and vitamin Adeprivation syndrome. Congenital stationary night blindness is aninherited eye disorder that principally affects the rod photoreceptorsin the retina, impairing night vision. There may also be moderate tohigh myopia (short sightedness). Under good lighting conditions, thereis usually no visual deficit. There are several different types of thedisorder which are inherited in an autosomal dominant, autosomalrecessive, or X-linked recessive manner. The X-linked type affectsalmost exclusively males and accounts for the predominance of males withcongenital stationary night blindness.

WO 2007/109824 discloses a process for preparing a stable packageddosage form comprising an oxidation-sensitive material such as carotenesand carotenoids in whole dried algae of the genus Dunaliella. The dosageform is described as being useful in the treatment of a plurality ofdiseases including optical disorders such as macular degeneration orcataracts.

J. Preston Van Hooser, Tomas S. Aleman, Yu-Guang He, Artur V. Cideciyan,Vladimir Kuksa, Steven J. Pittler, Edwin M. Stone, Samuel G. Jacobson,Krzysztof Palczewski (2000) Rapid restoration of visual pigment andfunction with oral retinoid in a mouse model of childhood blindness.PNAS, vol. 97 no. 15, 8623-8628, analyzed retinoid flow inRpe65-deficient mice, a model of Leber congenital amaurosis, which haveno rod photopigment and severely impaired rod physiology. Theyintervened by using oral 9-cis-retinal, attempting to bypass thebiochemical block caused by the genetic abnormality. Within 48 h, therewas formation of rod photopigment and dramatic improvement in rodphysiology.

J. Preston Van Hooser, Yan Liang, Tadao Maeda, Vladimir Kuksa, Geeng-FuJang, Yu-Guang He, Fred Rieke, Henry K. W. Fong, Peter B. Detwiler, andKrzysztof Palczewski (2002) Recovery of Visual Functions in a MouseModel of Leber Congenital Amaurosis. J. Biol. Chem., Vol. 277, Issue 21,19173-19182, provide evidence that early intervention by 9-cis-retinaladministration significantly attenuated retinal ester accumulation andsupported rod retinal function for more than 6 months post-treatment. Insingle cell recordings rod light sensitivity was shown to be a functionof the amount of regenerated isorhodopsin; high doses restored rodresponses with normal sensitivity and kinetics.

Syed M. Noorwez, Ritu Malhotra, J. Hugh McDowell, Karen A. Smith, MarkP. Krebs|, and Shalesh Kaushal (2004) Retinoids Assist the CellularFolding of the Autosomal Dominant Retinitis Pigmentosa Opsin MutantP23H. J. Biol. Chem., Vol. 279, Issue 16, 16278-16284, demonstrate thatthe mutant opsin P23H, associated with autosomal dominant retinitispigmentosa, is effectively rescued by 9- or 11-cis-retinal, the nativechromophore. P23H rhodopsins containing 9- or 11-cis-retinal hadblue-shifted absorption maxima and altered photo-bleaching propertiescompared with the corresponding wild-type proteins.

There is no description in the scientific literature of a treatmentcausing an improvement in day vision of an RP patient.

SUMMARY OF THE INVENTION

In a first aspect of the present invention, there is provided a methodfor improving day [photopic] vision and/or cone-derived visual field andvisual functions in a subject suffering from a retinal disease or traumacomprising administering to the subject a pharmaceutically effectiveamount of crude Dunaliella powder.

In the present specification, the term day vision or photopic visionrelates to vision in bright light generated by the central portion ofthe retina, as opposed to night vision which is generated by theperipheral portion of the retina. Day vision is predominantly mediatedby the cone cells in the retina.

In the present specification, the term retinal disease or trauma mayinclude all types of retinal dystrophies in which degeneration of theretina leads to deterioration in day vision. Acquired retinaldegenerations such as Age-related Macular Degeneration may also beincluded in this term. In one embodiment, retinal diseases which have anight vision stage or component are also included, but in such cases theinvention relates only to the day vision stage or component. In anotherembodiment, the retinal disease is a retinal degenerative disease.

The active ingredient in accordance with the invention is asubstantially crude Dunaliella algae preparation, typically driedDunaliella algae. The Dunaliella algae are preferably Dunaliellabardawil. Other species include D. salina, D. viridis, D. peircei, D.parva, D. media, D. euchlora, D. minuta, D. tertiolecta, D. primolecta,D. acidophila, D. quartolecta and D. polymorpha.

In a preferred embodiment, the substantially crude Dunaliella algaepreparation contains β-carotene (BC) at an approximately 1:1 ratio of9-cis to all-trans isomers of BC or greater than 1:1 ratio of 9-cis toall-trans isomers of BC.

The terms “treating” or “treatment” in the present specification shouldbe understood as bringing about an improvement in the pathologicalsymptoms of the disease, and in some cases curing the disease.

An “effective amount” should be understood as an amount or dose of theactive ingredient which is sufficient to achieve the desired therapeuticeffect, i.e. treatment of the indicated diseases. The effective amountdepends on various factors including the severity of the disease, theadministration regimen, e.g. whether the preparation is given once orseveral times over a period of time, the physical condition of thesubject; etc. The artisan should have no difficulties, by minimalexperiments, to determine the effective amount in each case.

The crude Dunaliella powder is preferably administered orally, forexample in an encapsulated form. However, other forms of administrationare contemplated such as Dunaliella powder formulated withpharmaceutically-acceptable excipients for topical, intravenous,intramuscular, intraperitoneal or subcutaneous administration.

Suggested medical conditions for treatment in accordance with thepresent teachings include the following:

Retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), Age-relatedmacular degeneration (AMD), recessive RP, Dominant retinitis pigmentosa,X-linked retinitis pigmentosa, Incomplete X-linked retinitis pigmentosa,dominant, Dominant Leber congenital amaurosis, Recessive ataxia,posterior column with retinitis pigmentosa, Recessive retinitispigmentosa with para-arteriolar preservation of the RPE, Retinitispigmentosa RP12, Usher syndrome, Dominant retinitis pigmentosa withsensorineural deafness, Recessive retinitis punctata albescens,Recessive Alström syndrome, Recessive Bardet-Biedl syndrome, Dominantspinocerebellar ataxia w/macular dystrophy or retinal degeneration,Recessive abetalipoproteinemia, Recessive retinitis pigmentosa withmacular degeneration, Recessive Refsum disease, adult form, RecessiveRefsum disease, infantile form, Recessive enhanced S-cone syndrome,Retinitis pigmentosa with mental retardation, Retinitis pigmentosa withmyopathy, Recessive Newfoundland rod-cone dystrophy, Retinitispigmentosa sinpigmento, Sector retinitis pigmentosa, Regional retinitispigmentosa, Senior-Loken syndrome, Joubert syndrome, Stargardt disease,juvenile, Stargardt disease, late onset, Dominant macular dystrophy,Stargardt type, Dominant Stargardt-like macular dystrophy, Recessivemacular dystrophy, Recessive fundus flavimaculatus, Recessive cone-roddystrophy, X-linked progressive cone-rod dystrophy, Dominant cone-roddystrophy, Cone-rod dystrophy; de Grouchy syndrome, Dominant conedystrophy, X-linked cone dystrophy, Recessive cone dystrophy, Recessivecone dystrophy with supernormal rod electroretinogram, X-linked atrophicmacular dystrophy, X-linked retinoschisis, Dominant macular dystrophy,Dominant radial, macular drusen, Dominant macular dystrophy, bull's-eye,Dominant macular dystrophy, butterfly-shaped, Dominant adult vitelliformmacular dystrophy, Dominant macular dystrophy, North Carolina type,Dominant retinal-cone dystrophy 1, Dominant macular dystrophy, cystoid,Dominant macular dystrophy, atypical vitelliform, Foveomacular atrophy,Dominant macular dystrophy, Best type, Dominant macular dystrophy, NorthCarolina-like with progressive, Recessive macular dystrophy, juvenilewith hypotrichosis, Recessive foveal hypoplasia and anterior segmentdysgenesis, Recessive delayed cone adaptation, Macular dystrophy in bluecone monochromacy, Macular pattern dystrophy with type II diabetes anddeafness, Flecked Retina of Kandori, Pattern Dystrophy, DominantStickler syndrome, Dominant Marshall syndrome, Dominant vitreoretinaldegeneration, Dominant familial exudative vitreoretinopathy, Dominantvitreoretinochoroidopathy; Dominant neovascular inflammatoryvitreoretinopathy, Goldmann-Favre syndrome, Recessive achromatopsia,Dominant tritanopia, Recessive rod monochromacy, Congenital red-greendeficiency, Deuteranopia, Protanopia, Deuteranomaly, Protanomaly,Recessive Oguchi disease, Dominant macular dystrophy, late onset,Recessive gyrate atrophy, Dominant atrophia greata, Dominant centralareolar choroidal dystrophy, X-linked choroideremia, Choroidal atrophy,Central areolar, Central, Peripapillary, Dominant progressive bifocalchorioretinal atrophy, Progresive bifocal Choroioretinal atrophy,Dominant Doyne honeycomb retinal degeneration (Malattia Leventinese),Amelogenesis imperfecta, Recessive Bietti crystalline corneoretinaldystrophy, Dominant hereditary vascular retinopathy with Raynaudphenomenon and migraine, Dominant Wagner disease and erosivevitreoretinopathy, Recessive microphthalmos and retinal diseasesyndrome; Recessive nanophthalmos, Recessive retardation, spasticity andretinal degeneration, Recessive Bothnia dystrophy, Recessivepseudoxanthoma elasticum, Dominant pseudoxanthoma elasticum; RecessiveBatten disease (ceroid-lipofuscinosis), juvenile, Dominant Alagillesyndrome, McKusick-Kaufman syndrome, hypoprebetalipoproteinemia,acanthocytosis, palladial degeneration; Recessive Hallervorden-Spatzsyndrome; Dominant Sorsby's fundus dystrophy, Oregon eye disease,Kearns-Sayre syndrome, Retinitis pigmentosa with developmental andneurological abnormalities, Basseb Korenzweig Syndrome, Hurler disease,Sanfilippo disease, Scieie disease, Melanoma associated retinopathy,Sheen retinal dystrophy, Duchenne macular dystrophy, Becker maculardystrophy, Birdshot Retinochoroidopathy, Multiple Evanescent White-dotsyndrome, Acute Zonal Occult Outer Retinopathy, Retinal vein occlusion,Retinal artery occlusion, Diabetic retinopathy, Retinal toxicity,Retinal injury, Retinal traumata and Retinal laser lesions, and FundusAlbipunctata.

As used herein, the term “age-related macular degeneration or dystrophy”or “AMD” refers to a debilitating disease, which include wet and dryforms of AMD. The dry form of AMD, which accounts for about 90 percentof all cases, is also known as atrophic, nonexudative, or drusenoidmacular degeneration. With the dry form of AMD, drusen typicallyaccumulate in the retinal pigment epithelium (RPE) tissue beneath/withinthe Bruch's membrane. Vision loss can then occur when drusen interferewith the function of photoreceptors in the macula. The dry form of AMDresults in the gradual loss of vision over many years. The dry form ofAMD can lead to the wet form of AMD. The wet form of AMD can progressrapidly and cause severe damage to central vision. The maculardystrophies include Stargardt Disease, also known as Stargardt MacularDystrophy or Fundus Flavimaculatus, which is the most frequentlyencountered juvenile onset form of macular dystrophy, and Best dystrophyalso known as vitelliform macular dystrophy, cone-rod dystrophy andothers included in the list above.

A further embodiment of this aspect of the invention is a pharmaceuticalcomposition for improving day vision and/or visual field in a subjectsuffering from a retinal degenerative disease comprising crudeDunaliella powder.

In a second aspect of the present invention, there is provided a methodfor improving night vision and/or rod derived visual field in a subjectsuffering from a retinal night vision disease comprising administeringto the subject a pharmaceutically effective amount of crude Dunaliellapowder. Patients with this disease have difficulty adapting to low lightsituations due to impaired photoreceptor transmission.

In the present specification, the term night vision relates to vision indim light generated by the peripheral portion of the retina. Nightvision is predominantly mediated by the rod cells in the retina.

In the present specification, the term retinal disease may include alltypes of retinal dystrophies which are stationary and which lead todeterioration in night vision. Examples of such diseases includecongenital night vision disorder, congenital stationary night blindness,fundus albipunctatus and vitamin A deprivation syndrome. In oneembodiment, retinal degenerative diseases which have a day vision stageor component are also included, but in such cases the invention relatesonly to the night vision stage or component. In another embodiment, theretinal disease is a retinal degenerative disease.

The active ingredient in accordance with the invention is asubstantially crude Dunaliella algae preparation, typically driedDunaliella algae. The Dunaliella algae are preferably Dunaliellabardawil. Other species include D. salina, D. viridis, D. peircei, D.parva, D. media, D. euchlora, D. minuta, D. tertiolecta, D. primolecta,D. acidophila, D. quartolecta and D. polymorpha.

In a preferred embodiment, the substantially crude Dunaliella algaepreparation contains β-carotene (BC) at an approximately 1:1 ratio of9-cis to all-trans isomers of BC or greater than 1:1 ratio of 9-cis toall-trans isomers of BC.

The meanings of the terms “treating”, “treatment” and “effective amount”are as defined above.

A further embodiment of this aspect of the invention is a pharmaceuticalcomposition for improving night vision and/or rod-derived visual fieldin a subject suffering from a retinal degenerative disease comprisingcrude Dunaliella powder.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to understand the invention and to see how it may be carriedout in practice, embodiments will now be described, by way ofnon-limiting example only, with reference to the accompanying drawings,in which:

FIG. 1 is a dark-adapted chromatic visual field diagram of the left eyeof an RP patient before treatment;

FIG. 2 is a dark-adapted chromatic visual field diagram of the left eyeof an RP patient after 3 months of treatment;

FIG. 3 is a dark-adapted chromatic visual field diagram of the right eyeof an RP patient before treatment;

FIG. 4 is a dark-adapted chromatic visual field diagram of the right eyeof an RP patient after 3 months treatment;

FIG. 5 is a bar graph showing photoreceptor ERG response levelspre-treatment, after treatment and after a washout period of 3 months inthe left and right eyes of an RP patient;

FIG. 6 is a dark-adapted chromatic visual field diagram of the right eyeof patient #4 before (A) and after 3 months (B) of Dunaliella treatmentshowing the Scotoma (blind spot);

FIG. 7 is a bar graph showing the visual field mean deviation before andafter treatment of normal subjects and patients; and

FIG. 8 is a bar graph showing the b-wave amplitude maximal responsesbefore and after treatment of normal subjects and patients.

DETAILED DESCRIPTION OF EMBODIMENTS

All of the human studies described below employed capsules containingDunaliella powder prepared as follows.

Dunaliella bardawil (hereinafter “Db”) was grown and cultivated in largebody open salt water ponds of 50,000 m² to obtain algae comprisingapproximately 8% by weight of β-carotene (hereinafter “BC”) at anapproximately 1:1 ratio of 9-cis and all-trans isomers of BC, or greaterthan 1:1 ratio of 9-cis and all-trans isomers of BC. The algae wereharvested by dislodging centrifuges into a concentrated paste. The pastewas washed to remove the salt and sterilized, and then spray dried toyield Db powder comprising approximately 8% BC and less than 5%moisture. The powder was packaged in capsules of 250-300 mg algaecontaining 15-20 mg of BC each together with all of the naturalcomponents of the algae. The BC of the capsules retains the originalratio of isomers. The capsules are packaged in vacuum closed blisterswhich have a shelf life of up to three years.

EXAMPLE I The Effect of Oral Administration of 9-Cis Rich Powder of theAlga Dunaliella bardawil on Day Vision Visual Functions in Patients withRP

In a double-blind, placebo controlled, cross-over designed clinicaltrial, 20 patients (ages 50-75) with autosomal dominant retinitispigmentosa (with RHO mutation) received 2 capsules twice a day for 12weeks. Half of the patients received Dunaliella baraweil while the otherhalf received placebo. The treatment period will be followed by a 12week washout period and subsequently by a further 12 week period inwhich the patients who received Dunaliella baraweil will receiveplacebo, and vica versa. Four patients completed the first treatmentperiod.

Results: out of 5 of the patients who completed the course of thetreatment, two patients (#2 & #5) showed no improvement. On the otherhand, the visual functions of the three other patients improveddramatically both objectively (ERG) and subjectively (visual fields andpatients' report). These are unprecedented results for RP. It is assumedthat these patients received the Dunaliella treatment.

One patient showed an improvement of 30% in photopic electroretinography(ERG) responses. Results for a second patient (#4) are presented inFIGS. 1-5. FIGS. 1-4 show the dark-adapted chromatic visual fields ofthe left and right eyes of the patient before and after the treatment.The subject is looking at the center and the observer shows him a smalllight stimulus in the periphery. The colored circles represent when thesubject first observes the stimuli. Red stimulus is represented by a redcircle and blue stimulus is represented by blue. The numbers II3C meanssize II (smaller compared to V), 3C represents the light intensity andthe dash above C represents 100 times smaller light intensity.

Relative Intensity 1 0.0315 2 0.100 3 0.315 4 1.00 a 0.40 b 0.50 c 0.63d 0.90 e 1.00 Object mm² O 1/16 I ¼  II 1 III 4 IV 18 V 64

Photoreceptor ERG results are presented in FIG. 5. It may be seen thatboth eyes showed marked improvement after treatment. The ERG returned topretreatment levels 3 months after cessation of treatment. Thisindicates that maintenance treatment is required to maintain visualfunction.

EXAMPLE II Further Results in the Day (Cone) Vision of Patients Enrolledin the Clinical Trial of Example I

Additional patients subsequently completed the 3 month treatment period.The visual field and electrical function results for 5 patients arepresented in Tables 1 and 2.

TABLE 1 Central (cone derived) visual field area Right Eye Left EyePatient Pretreatment Post treatment Pretreatment Post treatment 1 9 19 914 2 184 185 189 183 3 90 131 96 141 4 159 159 145 137 5 164 165 177 185

TABLE 2 Cone electrical function (in μV) Right Eye Left Eye PatientPretreatment Post treatment Pretreatment Post treatment 1 10 13 10 10 210 8 10 7 3 15 15 9 19 4 9 19 11 19 5 17 25 27 25

From the above results it may be seen that Patient #3 showed significantimprovement in the visual field in both eyes and the ERG of one eye.Patients # 4 showed no change in the cone derived area which was alreadywithin the normal limits prior to treatment. However, the blind spot inthe right eye decreased significantly by a factor of 3.5 (FIG. 6). Thecone electrical function showed significant improvement in patient #4 aswell as in one of the eyes of patient #3. It is assumed that thesepatients received the Dunaliella treatment. There was no appreciableimprovement in patients #2 &5.

EXAMPLE III The Effect of Oral Administration of 9-Cis Rich Powder ofthe Alga Dunaliella Bardawil on Visual Functions in Patients with DryAge-Related Macular Degeneration (AMD)

A clinical trial similar to the one described in Example I above will becarried out with patients with dry Age-related Macular Degeneration.

A preliminary study was carried out with a 74 years old woman sufferingfrom a years-long deteriorating AMD in both eyes. The woman has not beenable to read for the last few years. Within a week of receiving theDunaliella treatment at a dose of 4 capsules daily, she returned tonormal reading in both eyes, although there was no improvement in themorphological appearance in ophthalmoscopy and OCT.

EXAMPLE IV The Effect of Oral Administration of 9-Cis Rich Powder of theAlga Dunaliella Bardawil on Visual Functions in Patients with CongenitalStationary Night Blindness

Subjects

Normal subjects: Five subjects without any pathology under ophthalmicexamination, aged 58.6±5.6 years old, were treated daily for ninety dayswith four capsules of Dunaliella Bardawil as described above. Thesubjects were tested before treatment and after ninety days of treatmentfor visual acuity, biomicroscopic examination intraocular pressure andelectroretinogram (ERG) tests. Normal subjects and patients performedvisual fields central 24-2 threshold test before and after treatment inboth eyes (the amblyopic eye was excluded).

Patients: Five patients, age 32±11 years old, with clinically andgenetically diagnosed Congenital stationary night blindness (CSNB) weretreated daily with four capsules of Dunaliella bardawil for 90 days.

The subjects were tested bilaterally before and after treatment by ERG(LKC Technologies, Inc., Gaithersburg, Md.) using an ISCEV compliantprotocol. The scotopic responses were recorded for dim single flashstimulus (0.023 cd−s/m2) and bright single flash stimulus (2.44cd−s/m2). Light adaptation for 10 minutes of white background light(0.023 cd−s/m2) followed by white single flash stimulus (2.44 cd−s/m2)and white 2.44 cd−s/m2 30 Hz flicker. The patients were dark adapted foran additional 90 minutes after recording the scotopic ERG 30 minutes(total of 120 minutes dark adaptation) and were then light adapted. Theamplitudes latencies of the wave form were measured and the percentagesof change were calculated by subtraction of baseline ERG responses frompost treatment responses and divided by the baseline responses for eacheye.

Results

Prior to the treatment, the best-corrected visual acuity for all normalsubjects and patients were 20/20 in both eyes except for one patient whohad amblyopic eye with visual acuity of 20/200. The visual acuity didnot change post treatment.

The averaged mean deviation before and after treatment did not show anystatistical significant improvement for the normal subject group(T-test, p=0.291). Prior to treatment, the patients' averaged visualfield mean deviation was −5.16±2.25. After treatment, the mean deviationimproved significantly to −3.42±3.12 (T-test, p=0.019).

The results are summarized in FIG. 7.

Electroretinogram (ERG)

Normal subjects: The ERG percentage of change responses of the normalsubjects are summarized in Table 3. The average isolated rod responseamplitude pre-treatment was 199±57 μV and post-treatment was 184±49 μV(p=0.340, T-test). The maximal scotopic a-wave and b-wave amplituderesponses did not show any difference from baseline. The average a-wavepre-treatment was 186±61 μV and post-treatment was 181±28 μV (p=0.307,T-test). The average b-wave amplitude pre-treatment was 361±61 μV andpost-treatment was 370±79 μV (p=0.615, T-test). The ERG responses inphotopic conditions did not show any significant change from baseline.The average a-wave amplitude pre-treatment was 28±4 μV andpost-treatment was 25±5 μV (p=0.451, T-test). The average b-waveamplitude pre-treatment was 106±24 μV and post-treatment was 108±26 μV(p=0.797, T-test). The 30 Hz flicker responses did not show significantdifferences from baseline with pre-treatment average amplitude of 73±12μV and post-treatment average amplitude of 86±16 μV (p=0.099, T-test).However, one subject showed a clinical significant improvement of 90% inthe 30 Hz response in both eyes. This improvement could not bestatically evaluated in this small group of subjects.

TABLE 3 ERG percentage of change Averaged percentage of Conditionschange from baseline Scotopic Isolated rod response (b- 3 ± 21% waveamplitude) Maximal a-wave amplitude −3 ± 8%  Maximal b-wave amplitude 2± 14% Photopic a-wave amplitude 3 ± 23% b-wave amplitude 4 ± 25% 30 HzFlicker 22 ± 37% 

Patients: The responses for the CSNB patients are summarized in Table 4.The maximal scotopic ERG responses for 30 minutes dark adaptation werenot changed significantly from baseline (the a- and b-waves maximal rodresponses were 15%±55% and 42%±109% respectively). However, the 120minutes dark adaptation maximal ERG b-wave responses was doubled, the a-and b-waves maximal rod responses increased by 17%±52% and 68%±63%respectively. The average b-wave maximal response amplitudepre-treatment was 194±56 μV and post-treatment was 300±52 μV (p<0.001,T-test). After 120 minutes of dark adaptation the average isolated rodresponse b-wave amplitude improved from 86±40 μV at baseline to 184±105μV after treatment (p<0.001, T-test). All patients demonstrated aclinically significant improvement in the b-wave maximal and Isolatedrod responses amplitude which was found to be similar in both eyes ofeach patient. The photopic single flash a- and b-wave response and 30 Hzflicker response (Table 4) did not show significant differences(0.11-0.571).

TABLE 4 ERG responses Averaged percentage of Conditions change frombaseline Scotopic 30 Isolated rod response (b- None measurable Minutesdark wave amplitude) adaptation Maximal a-wave amplitude 15 ± 55%Maximal b-wave amplitude  42 ± 109% Scotopic 120 Isolated rod response(b- 112 ± 61%  Minutes dark wave amplitude) adaptation Maximal a-waveamplitude 17 ± 52% Maximal b-wave amplitude 68 ± 63% Photopic a-waveamplitude 18 ± 59% b-wave amplitude 29 ± 63% 30 Hz Flicker −11 ± 33% 

The results are summarized in FIG. 8.

Conclusions: Oral treatment with the algae Dunaliella bardawilsignificantly improved dark adaptation function in a number ofcongenital stationary night blindness patients.

Example V Results in the Night Vision of Patients Enrolled in theClinical Trial of Example I

The night and peripheral vision field and electrical function resultsfor the patients of Example II are presented in Tables 5 and 6.

TABLE 5 Visual field areas Right Eye Left Eye Patient Pretreatment Posttreatment Pretreatment Post treatment 1 7 7 9 7 2 97 143 102 123 3 61 6461 68 4 18 130 22 127 5 137 165 113 139

TABLE 6 Rod electrical function (in μV) Right Eye Left Eye PatientPretreatment Post treatment Pretreatment Post treatment 1 11 11 11 11 220 21 25 25 3 23 30 21 26 4 10 48 16 106 5 15 15 21 36

The results show a significant improvement of the rod derived visualfield area in both eyes of patient #4 and to a lesser extent in patients#2 & #5. The rod electrical function significantly improved in both eyesin patient #4 and to a lesser extent in the left eye of patient #5. Itis assumed that these patients received the Dunaliella treatment.

The invention claimed is:
 1. A method for improving day vision and/orcone-derived visual field and visual function in a subject sufferingfrom a retinal disease comprising administering to a subject in needthereof a pharmaceutically effective amount of a capsule dosage formcomprising crude Dunaliella powder that is filled in a capsule undernormal atmosphere to produce the capsule dosage form, the crudeDunaliella powder comprising β-carotene at an approximately 1:1 ratio of9-cis and all-trans β-carotene isomers, or a greater than 1:1 ratio of9-cis and all-trans β-carotene isomers.
 2. The method of claim 1,wherein the retinal disease is selected from the group consisting ofretinitis pigmentosa (RP); Leber congenital amaurosis (LCA), recessiveRP; Dominant retinitis pigmentosa; X-linked retinitis pigmentosa;Incomplete X-linked retinitis pigmentosa, dominant; Dominant Lebercongenital amaurosis; Recessive ataxia, posterior column with retinitispigmentosa; Recessive retinitis pigmentosa with para-arteriolarpreservation of the retinal pigment epithelial (RPE); Retinitispigmentosa RP12; Usher syndrome; Dominant retinitis pigmentosa withsensorineural deafness; Recessive retinitis punctata albescens;Recessive Alstrom syndrome; Recessive Bardet-Biedl syndrome; Dominantspinocerebellar ataxia with macular dystrophy or retinal degeneration;Recessive abetalipoproteinemia; Recessive retinitis pigmentosa withmacular degeneration; Recessive Refsum disease, adult form; RecessiveRefsum disease, infantile form; Recessive enhanced S-cone syndrome;Retinitis pigmentosa with mental retardation; Retinitis pigmentosa withmyopathy; Recessive Newfoundland rod- cone dystrophy; Retinitispigmentosa sine pigmento; Sector retinitis pigmentosa; Regionalretinitis pigmentosa; Senior-Loken syndrome; Joubert syndrome; Stargardtdisease, juvenile; Stargardt disease, late onset; Dominant maculardystrophy, Stargardt type; Dominant Stargardt-like macular dystrophy;Recessive macular dystrophy; Recessive fundus flavimaculatus; Recessivecone-rod dystrophy; X-linked progressive cone-rod dystrophy; Dominantcone-rod dystrophy; Cone-rod dystrophy; de Grouchy syndrome; Dominantcone dystrophy; X-linked cone dystrophy; Recessive cone dystrophy;Recessive cone dystrophy with supernormal rod electroretinogram;X-linked atrophic macular dystrophy; X-linked retinoschisis; Dominantmacular dystrophy; Dominant radial, macular drusen; Dominant maculardystrophy, bull's-eye; Dominant macular dystrophy, butterfly- shaped;Dominant adult vitelliform macular dystrophy; Dominant maculardystrophy, North Carolina type; Dominant retinal-cone dystrophy 1;Dominant macular dystrophy, cystoid; Dominant macular dystrophy,atypical vitelliform; Foveomacular atrophy; Dominant macular dystrophy,Best type; Dominant, progressive North Carolina macular dystrophy;Recessive macular dystrophy, juvenile with hypotrichosis; Recessivefoveal hypoplasia and anterior segment dysgenesis; Recessive delayedcone adaptation; Macular dystrophy in blue cone monochromacy; Macularpattern dystrophy with type II diabetes and deafness; Flecked Retina ofKandori; Pattern Dystrophy; Dominant Stickler syndrome; DominantMarshall syndrome; Dominant vitreoretinal degeneration; Dominantfamilial exudative vitreoretinopathy; Dominantvitreoretinochoroidopathy; Dominant neovascular inflammatoryvitreoretinopathy; Goldmann-Favre syndrome; Recessive achromatopsia;Dominant tritanopia; Recessive rod monochromacy; Congenital red-greendeficiency; Deuteranopia; Protanopia; Deuteranomaly; Protanomaly;Recessive Oguchi disease; Dominant macular dystrophy, late onset;Recessive gyrate atrophy; Dominant atrophia areata; Dominant centralareolar choroidal dystrophy; X-linked choroideremia; Peripapillarychoroidal atrophy; Dominant progressive bifocal chorioretinal atrophy;Progressive bifocal Choroioretinal atrophy; Dominant Doyne honeycombretinal degeneration or Malattia Leventinese syndrome; Amelogenesisimperfecta; Recessive Bietti crystalline corneoretinal dystrophy;Dominant hereditary vascular retinopathy with Raynaud phenomenon andmigraine; Dominant Wagner disease and erosive vitreoretinopathy;Recessive microphthalmos and retinal disease syndrome; Recessivenanophthalmos; Recessive retardation, spasticity and retinaldegeneration; Recessive Bothnia dystrophy; Recessive pseudoxanthomaelasticum; Dominant pseudoxanthoma elasticum; Recessive Batten orJuvenile neuronal ceroid-lipofuscinosis; Dominant Alagille syndrome;McKusick-Kaufman syndrome; hypoprebetalipoproteinemia, acanthocytosis,palladial degeneration; Recessive Hallervorden-Spatz syndrome; DominantSorsby's fundus dystrophy; Oregon eye disease; Kearns-Sayre syndrome;Retinitis pigmentosa with developmental and neurological abnormalities;Bassen-Korenzweig Syndrome; Hurler disease; Sanfilippo disease; Scheiedisease; Melanoma associated retinopathy; Sheen retinal dystrophy;Duchenne macular dystrophy; Becker macular dystrophy; BirdshotRetinochoroidopathy; Multiple Evanescent White-dot syndrome; Acute ZonalOccult Outer Retinopathy; Retinal vein occlusion; Retinal arteryocclusion; Diabetic retinopathy; and Fundus Albipunctatus.
 3. The methodof claim 1, wherein the crude Dunaliella powder is administered orally.4. The method of claim 1, wherein the Dunaliella is selected from thegroup consisting of Dunaliella bardawil, D. salina, D. viridis, D.peircei, D. parva, D. media, D. euchlora, D. minuta, D. tertiolecta, D.primolecta, D. acidophila, D. quartolecta and D. polymorpha.
 5. Themethod of claim 1, wherein the retinal disease is age-related maculardegeneration (AMD).
 6. The method according to claim 1, wherein thecapsule dosage form comprises crude Dunaliella powder present in anamount of from 250 to 300 milligrams (mg).
 7. The method according toclaim 6, wherein the crude Dunaliella powder comprises 8% β-carotene. 8.The method according to claim 1, wherein the crude Dunaliella powdercomprises moisture.
 9. The method according to claim 6, wherein thecrude Dunaliella powder comprises 15-20 mg of β-carotene.
 10. The methodaccording to claim 6, wherein the crude Dunaliella powder comprises allnatural components of the algae.
 11. A method for improving day visionand/or cone-derived visual field and visual function in a subjectsuffering from Retinitis pigmentosa, comprising: administering to asubject in need thereof a pharmaceutically effective amount of a capsuledosage form comprising crude Dunaliella powder encapsulated under normalatmosphere, the crude Dunaliella powder comprising β-carotene at anapproximately 1:1 ratio of 9-cis and all-trans β-carotene isomers, or agreater than 1:1 ratio of 9-cis and all-trans β-carotene isomers.